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Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19A Meta-analysis

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Key Points

Question  Is administration of IL-6 antagonists associated with 28-day all-cause mortality in patients hospitalized for COVID-19?

Findings  This prospective meta-analysis of 27 randomized trials included 10 930 patients, of whom 2565 died by 28 days. The 28-day all-cause mortality was lower among patients who received IL-6 antagonists compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary odds ratios for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids vs 1.09 without administration of corticosteroids.

Meaning  Administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in patients hospitalized for COVID-19.

Abstract

Importance  Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective  To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data Sources  Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study Selection  Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data Extraction and Synthesis  In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main Outcomes and Measures  The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results  A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions and Relevance  In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Trial Registration  PROSPERO Identifier: CRD42021230155

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Article Information

Corresponding Author: Manu Shankar-Hari, MSc, PhD, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust London, East Wing, London SE17EH, England (manu.shankar-hari@kcl.ac.uk).

Accepted for Publication: June 24, 2021.

Published Online: July 6, 2021. doi:10.1001/jama.2021.11330

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group authors and collaborators: Manu Shankar-Hari, PhD, MSc; Claire L. Vale, PhD; Peter J. Godolphin, PhD; David Fisher, MSc; Julian P. T. Higgins, PhD; Francesca Spiga, PhD; Jelena Savović, PhD; Jayne Tierney, PhD; Gabriel Baron, PhD; Julie S. Benbenishty, PhD; Lindsay R. Berry, PhD; Niklas Broman, MD; Alexandre Biasi Cavalcanti, MD; Roos Colman, MSc; Stefanie L. De Buyser, PhD; Lennie P. G. Derde, MD, PhD; Pere Domingo, PhD; Sharifah Faridah Omar, MD; Ana Fernandez-Cruz, MD, PhD; Thijs Feuth, MD, PhD; Felipe Garcia, MD, PhD; Rosario Garcia-Vicuna, PhD; Isidoro Gonzalez-Alvaro, PhD; Anthony C. Gordon, MBBS, MD; Richard Haynes, DM; Olivier Hermine, MD, PhD; Peter W. Horby, MBBS; Nora K. Horick, MS; Kuldeep Kumar, MSc; Bart N. Lambrecht, MD, PhD; Martin J. Landray, PhD; Lorna Leal, MD, PhD; David J. Lederer, MD; Elizabeth Lorenzi, PhD; Xavier Mariette, MD, PhD; Nicolas Merchante, MD, PhD; Nor Arisah Misnan, MMed; Shalini V. Mohan, MD; Michael C. Nivens, PhD; Jarmo Oksi, MD, PhD; Jose A. Perez-Molina, PhD; Reuven Pizov, MD; Raphael Porcher, PhD; Simone Postma, MD; Reena Rajasuriar, PhD; Athimalaipet V. Ramanan, MD; Philippe Ravaud, MD, PhD; Pankti D. Reid, MD, MPH; Abraham Rutgers, MD, PhD; Aranzazu Sancho-Lopez, MD, PhD; Todd B. Seto, MD; Sumathi Sivapalasingam, MD; Arvinder Singh Soin, MS; Natalie Staplin, PhD; John H. Stone, MD, MPH; Garth W. Strohbehn, MD; Jonas Sunden-Cullberg, MD, PhD; Julian Torre-Cisneros, PhD; Larry W. Tsai, MD; Hubert van Hoogstraten, MD, PhD; Tom van Meerten, MD, PhD; Viviane Cordeiro Veiga, PhD; Peter E. Westerweel, MD, PhD; Srinivas Murthy, MD, CM, MHSc; Janet V. Diaz, MD; John C. Marshall, MD; Jonathan A. C. Sterne, PhD.

Affiliations of The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group authors and collaborators: Guy’s and St Thomas’ NHS Foundation Trust, ICU Support Offices, St Thomas’ Hospital, London, England (Shankar-Hari); School of Immunology and Microbial Sciences, Kings College London, London, England (Shankar-Hari); University College London, MRC Clinical Trials Unit at UCL, London, England (Vale, Godolphin, Fisher, Tierney); Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England (Higgins, Savović, Sterne); NIHR Bristol Biomedical Research Centre, Bristol, England (Higgins, Sterne); National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England (Higgins, Savović); University of Bristol, Bristol, England (Spiga); Assistance Publique–Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France (Baron, Porcher, Ravaud); INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France (Baron, Porcher, Ravaud); Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel (Benbenishty); Berry Consultants, Austin, Texas (Berry, Lorenzi); Turku University Hospital, Department of Infectious Diseases, Turku, Finland (Broman, Oksi); BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil (Cavalcanti, Veiga); Department of Public Health and Primary Care, Ghent University, Ghent, Belgium (Colman, De Buyser); Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands (Derde); Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Domingo); Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia (Omar, Rajasuriar); Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain (Fernandez-Cruz); Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland (Feuth); Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain (Garcia, Leal); Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain (Garcia-Vicuna, Gonzalez-Alvaro); Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England (Gordon); Nuffield Department of Population Health, University of Oxford, Oxford, England (Haynes, Landray, Staplin); MRC Population Health Research Unit, University of Oxford, Oxford, England (Haynes, Landray, Staplin); Department of Hematology, Necker Hospital, Paris, France (Hermine); Imagine Institute, University of Paris, INSERM U1153, Paris, France (Hermine); Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England (Horby); International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England (Horby); Pandemic Sciences Centre, University of Oxford, Oxford, England (Horby); Department of Medicine, Massachusetts General Hospital, Boston (Horick); Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India (Kumar, Soin); Research Department, Medanta Institute of Education and Research, Gurugram, India (Kumar); VIB Center for Inflammation Research, Ghent University, Ghent, Belgium (Lambrecht); Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium (Lambrecht); Regeneron Pharmaceuticals Inc, Tarrytown, New York (Lederer, Nivens, Sivapalasingam); Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France (Mariette); Department of Rheumatology, Assistance Publique–Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France (Mariette); Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain (Merchante); Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia (Misnan); Genentech, South San Francisco, California (Mohan, Tsai); Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain (Perez-Molina); Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel (Pizov); University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France (Porcher, Ravaud); Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands (Postma, Rutgers); Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia (Rajasuriar); Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England (Ramanan); Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois (Reid); Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain (Sancho-Lopez); Center for Outcomes Research and Evaluation, Queen’s Medical Center, Honolulu, Hawaii (Seto); Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston (Stone); Department of Medicine (Rheumatology), Massachusetts General Hospital, Boston (Stone); VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan (Strohbehn); Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden (Sunden-Cullberg); Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain (Torre-Cisneros); Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey (van Hoogstraten); Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands (van Meerten); Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands (Westerweel); Department of Pediatrics, University of British Columbia, Vancouver, Canada (Murthy); Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland (Diaz); Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (Marshall); Health Data Research UK South-West, Bristol, England (Sterne).

Author Contributions: Dr Vale had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Shankar-Hari and Vale contributed equally.

Concept and design: Shankar-Hari, Vale, Godolphin, Tierney, Misnan, Benbenishty, Omar, Garcia, Garcia-Vicuna, Gordon, Hermine, Perez-Molina, Pizov, Rajasuriar, Reid, Sancho-Lopez, Stone, Tsai, Veiga, Murthy, Diaz, Marshall, Sterne.

Acquisition, analysis, or interpretation of data: Shankar-Hari, Vale, Godolphin, Fisher, Higgins, Spiga, Savovic, Misnan, Baron, Benbenishty, Berry, Broman, Biasi Cavalcanti, Colman, De Buyser, Domingo, Derde, Omar, Fernández-Cruz, Feuth, Garcia, Garcia-Vicuna, Gonzalez-Alvaro, Gordon, Haynes, Hermine, Horby, Horick, Kumar, Lambrecht, Landray, Leal, Lederer, Lorenzi, Mariette, Merchante, Mohan, Nivens, Oksi, Perez-Molina, Pizov, Porcher, Postma, Rajasuriar, Ramanan, Ravaud, Reid, Rutgers, Seto, Sancho-Lopez, Sivapalasingam, Soin, Staplin, Strohbehn, Sunden-Cullberg, Torre-Cisneros, Tsai, van Hoogstraten, van Meerten, Veiga, Westerweel, Murthy, Marshall, Sterne.

Drafting of the manuscript: Shankar-Hari, Vale, Higgins, Baron, Benbenishty, Omar, Kumar, Pizov, Postma, Rajasuriar, Reid, Murthy, Sterne.

Critical revision of the manuscript for important intellectual content: Shankar-Hari, Vale, Godolphin, Fisher, Higgins, Spiga, Savovic, Tierney, Misnan, Baron, Berry, Broman, Biasi Cavalcanti, Colman, De Buyser, Domingo, Derde, Fernández-Cruz, Feuth, Garcia, Garcia-Vicuna, Gonzalez-Alvaro, Gordon, Haynes, Hermine, Horby, Horick, Lambrecht, Landray, Leal, Lederer, Lorenzi, Mariette, Merchante, Mohan, Nivens, Oksi, Perez-Molina, Porcher, Ramanan, Ravaud, Reid, Rutgers, Seto, Sancho-Lopez, Sivapalasingam, Soin, Staplin, Strohbehn, Stone, Sunden-Cullberg, Torre-Cisneros, Tsai, van Hoogstraten, van Meerten, Veiga, Westerweel, Murthy, Diaz, Marshall, Sterne.

Statistical analysis: Shankar-Hari, Vale, Godolphin, Fisher, Spiga, De Buyser, Feuth, Gonzalez-Alvaro, Horick, Kumar, Lorenzi, Merchante, Nivens, Oksi, Postma, Sancho-Lopez, Strohbehn, Murthy, Sterne.

Obtained funding: Derde, Gordon, Hermine, Lambrecht, Lederer, Ravaud, Stone.

Administrative, technical, or material support: Shankar-Hari, Vale, Misnan, Benbenishty, Derde, Gordon, Horby, Leal, Lederer, Mariette, Mohan, Nivens, Rajasuriar, Ramanan, Ravaud, Sancho-Lopez, Tsai, Veiga, Westerweel, Murthy, Diaz.

Supervision: Shankar-Hari, Higgins, Benbenishty, Derde, Garcia, Gordon, Hermine, Lambrecht, Nivens, Oksi, Pizov, Sancho-Lopez, Stone, Torre-Cisneros, Westerweel, Murthy, Diaz, Marshall, Sterne.

Conflict of Interest Disclosures: Dr Shankar-Hari reported being supported by clinician scientist award NIHR-CS-2016-16-011 from the UK National Institute for Health Research. Dr Vale, Mr Fisher, and Dr Tierney reported being supported by grant MC_UU_12023/24 from the UK Medical Research Council. Dr Godolphin reported being fully supported and Mr Fisher was partially supported by grant RIA 16-ST2-020 from Prostate Cancer UK. Dr Higgins reported being supported by senior investigator award NF-SI-0617-10145 from the UK National Institute for Health Research. Drs Higgins and Savović were supported by grants from the UK National Institute for Health Research Applied Research Collaboration West. Drs Higgins and Sterne reported being supported by grants from the UK National Institute for Health Research Bristol Biomedical Research Centre, Weston NHS Foundation Trust, and the University of Bristol. Dr Berry reported receiving grants from Berry Consultants. Dr Derde reported being a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. Drs De Buyser and Lambrecht reported being supported by grants from Belgian Health Care Knowledge Centre. Dr Domingo reported receiving support from the General Subdirectorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; being co-financed by the European Regional Development Fund; receiving grant support from the Instituto de Salud Carlos III for the TOCOVID clinical trial; and receiving honoraria from Merck Sharp & Dohme, Gilead Sciences, ViiV Healthcare, Janssen, Cilag, Theratechnologies, and Roche. Dr Omar reported being supported by grants from the University of Malaya. Dr Garcia-Vicuna reported receiving grants and personal fees from Sanofi and Lilly. Dr Gonzalez-Alvaro reported receiving grants from Sanofi, Biohope, and Gebro; serving on advisory boards for Lilly and Sanofi; receiving personal fees from Lilly, Sanofi, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Abbvie, Pfizer, and Novartis; and owning stock in PharmaMar. Dr Gordon reported being supported by grants from the UK National Institute for Health Research and the European Union and receiving personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. Dr Haynes reported receiving study drugs from Roche and receiving grants from Novartis and Boehringer Ingelheim. Dr Hermine reported receiving grants from Celgene, Bristol Myers Squibb, Alexion, Inatherys, and AB Science. Dr Horby reported receiving study drugs from Roche. Dr Horby reported being supported by grants from UK Research and Innovation–National Institute for Health Research. Dr Lambrecht reported receiving consultancy fees from GlaxoSmithKline, Sanofi, Argenx, Oncoarendi, and Novartis. Dr Landray reported receiving nonfinancial support from Roche and Regeneron and receiving grants from Boehringer Ingelheim, Novartis, and Janssen. Drs Lederer, Nivens, and Sivapalasingam reported being employees of and owning stock in Regeneron. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Mariette reported receiving personal fees from Bristol Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, and Sanofi and receiving grants from Biogen, Ose Pharmaceutical, and Pfizer. Dr Merchante reported receiving grants from Merck Sharp & Dome and personal fees from Gilead, Merck Sharp & Dome, and Shionogi for providing expert testimony. Drs Mohan and Tsai reported being employees of Genetech. Dr Nivens also reported receiving grants from the Biomedical Advanced Research and Development Authority. Dr Perez-Molina reported receiving grants from Roche Spain. Dr Ramanan reported receiving personal fees from Roche, Abbvie, Eli Lilly, Novartis, UCB, and the Swedish Orphan Biovitrum AB. Dr Ravaud reported being the primary investigator of the Corimmuno platform funded by the Ministry of Health in France. Drs Reid and Strohbehn reported being co-inventors of a filed patent (held by the University of Chicago) covering the use of low-dose tocilizumab for treatment of viral infections. Dr Staplin reported receiving study drugs from Roche and Regeneron and receiving grants from Boehringer Ingelheim. Dr Stone reported receiving grants from Roche/Genentech. Dr Strohbehn also reported being an employee of the US government. Dr Sunden-Cullberg reported receiving grants from the Swedish Research Council and the Center for Innovative Medicine. Dr Torre-Cisneros reported being supported by General Sub-Directorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; and being co-financed by the European Regional Development Fund. Dr Tsai also reported being involved with 2 patents pending that were filed and are owned by Genentech/Roche (one for a method to treating pneumonia, including COVID-19 pneumonia with an IL-6 antagonist, and another for tocilizumab and remdesivir combination therapy for COVID-19 pneumonia). Dr van Hoogstraten reported being an employee of and owning stock in Sanofi Genzyme. Dr Veiga reported receiving personal fees from Aspen Pharmacare, Cristália, and Pfizer for speaking and serving on advisory boards. Dr Murthy reported receiving grants from the Canadian Institutes of Health Research, Innovative Medicines Canada, and the Canadian Health Research Foundation. Dr Marshall reported receiving personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). Dr Sterne also reported being supported by grants from Health Data Research UK. No other disclosures were reported.

Funding/Support: Funding for administrative and communications support was provided by the World Health Organization.

Role of the Funder/Sponsor: The World Health Organization (WHO) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The WHO contributed to the design and conduct of the study by convening the WHO COVID-19 Clinical Management and Characterization Working Group. This group assembled information on ongoing trials and invited trial investigators to participate in this prospective meta-analysis. The WHO chief scientist invited trial investigators to participate and provided a secure portal for submission of data. Other than the contributions of Dr Diaz as a co-author, the WHO had no role in the preparation, review, or approval of the manuscript. The WHO had no role in the decision to submit the manuscript for publication.

Group Information: The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group nonauthor collaborators are listed in Supplement 14.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the opinions of the UK National Health Service, the UK National Institute for Health Research, UK Medical Research Council, the UK Department of Health and Social Care, or the US government.

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